hypertensive mammals may be treated to lower mean blood pressure by administering a calcium channel blocking agent together with one or both of a calcium supplement and Vitamin D. The hypotensive effect of this combination is synergistic and the dose response is more predictable than the administration of any of these agents singly.
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4. A pharmaceutical composition, comprising:
a) a blood pressure lowering effective amount of benzeneacetonitrile; and b) calcium in an amount which is at least five times, by mole, the amount of said benzeneacetonitrile.
1. A method of treatment of hypertensive mammals comprising the administration to a mammal in need of said treatment of
a) a blood pressure lowering effective amount of a benzeneacetonitrile; and b) a dietary calcium supplement in an amount which is at least five times, by mole, the amount of said benzeneacetonitrile.
3. A method of treatment according to
6. A pharmaceutical composition according to
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This application is a continuation of application Ser. No. 07/750,590 filed Aug. 27, 1991, now abandoned, which is a continuation-in-part of Ser. No. 07/460,482, filed Jan. 3, 1990, now abandonded.
Calcium channel blockers were identified as a method for the control of hypertension, as reported by Fleckenstein et al., Z. Kreislaufforsch, 56, 716 (1967), and are routinely used in the control of hypertension. Three calcium channel blockers are currently of clinical significance in the United States, verapamil, nifedipine and diltiazem. All three achieve their anti-hypertensive effect by inhibiting the entry of calcium ions into vascular smooth muscle. The ultimate effect is vasodilation.
Hypertensive hormones, such as the renin-angiotensin system (RAS), the vitamin D system, and the parathyroid hypertensive factor (PHF), are all causative factors in stimulating the increase of calcium ions in vascular smooth muscle. PHF is disclosed and described in copending patent application Serial No. 327,450.
It has been found that calcium supplements, in dietary form, may inhibit the RAS, PHF and vitamin D systems, [Park et al., Am. J. Physiol., 235, F22 (1978); Park et al., Am. J. Physiol., 240, F70 (1981); Hotchen et al., Am. J. Cardio., 62, 41G (1988); Bukoski et al., B.B.R.C., 147, 1330 (1987); Inoue et al., B.B.R.C., 152, 1388 (1988); Baran et al., J. Clin. Invest., 77, 1622 (1986); Lewanczuk et al., Am. J. Hypertens. (in press)] and are, therefore, beneficial in decreasing calcium uptake in vascular smooth muscle. An untoward effect of calcium supplementation is that the increased bio-availability of calcium partially negates the inhibitory effect on the endocrine system. Calcium channel blockers, by limiting the uptake of calcium in vascular smooth muscle, are beneficial, but have been found to stimulate some endocrine systems, such as the RAS system. [Kotchen et al., Am. J. Cardiol., 62 41G (1988); Matsumara et al., J. Pharmacol. Exp. Ther., 241, 1000 (1978); Resnick et al., Fed. Proc., 45, 2739 (1986)]. Utilization of calcium channel blockers may be limited by excessive vasodilation, negative inotropy, excessive depression of the sinus nodal rate, atrial-ventricular nodal conduction disturbances and interference with non-vascular smooth muscle contraction. A combination therapy which minimizes the amount of calcium channel blocker required to achieve the desired anti-hypertensive effect is desirable.
It now has been discovered that the use of supplemental dietary calcium and calcium channel blockers in combination is an effective method of treatment for hypertension and that the combination therapy employing both agents is more effective and predictable than the use of either agent alone. The effect is greater than the sum of the effects of both agents separately, or synergistic, with respect to dihydropyridines. One does not observe the synergistic effects with the benzeneacetonitriles; however, the present inventors have found that the combination therapy with benzeneacetonitriles and calcium gives a higher predictability of a dose response. That is, with a benzeneacetonitrile as the calcium channel blocker, a dose response relation is more apparent and there is smaller standard error, as compared to the other two classes of calcium channel blockers (i.e., dihydropyridines and benzothiazepines). Alternatively, the administration of compounds which are an effective form of Vitamin D, such as 1α,25-dihydroxycholecalciferol (1,25-(OH)2 D3), which increases intestinal calcium absorption, together with a calcium channel blocker of the dihydropyridine class, is a convenient treatment modality.
FIG. 1 illustrates the method of stimulating vascular smooth muscle contraction by systems which increase calcium uptake.
FIG. 2 illustrates the beneficial and damaging effects of calcium supplementation alone.
FIG. 3 illustrates the beneficial and damaging effects of calcium antagonists.
FIG. 4 illustrates the advantages of combination therapy.
We have discovered that a significant number of hypertensive mammals, including 30-40% of humans hypertensive [Resnick et al., 13th Meeting Int'l. Soc. of Hypertens.; J. Hypertens. (in press)], have measurable levels of a parathyroid-derived hormone which increases the uptake of calcium ions in vascular tissues. This factor, which we have named parathyroid hypertensive factor, or PHF, has been isolated from spontaneously hypertensive rats (SHR) and a similar substance has been identified in human hypertensives. Application Ser. No. 327,450, which is incorporated herein by reference, describes the characteristics of PHF and discloses methods for its identification.
It has been found that the production of PHF(s), as well as renin, can be inhibited by supplemental calcium and that increased levels of supplemental calcium are effective in reducing hypertension. The effects of calcium supplementation are unpredictable due to the fact that high levels of calcium in the blood may increase the bio-availability of calcium to vascular smooth muscle tissue, limiting the anti-hypertensive effect. In addition, very high levels of dietary calcium may result in undesirable and painful calcium deposits in joints and may lead to kidney stones.
The use of combination therapy involving both certain classes of calcium channel blockers and dietary calcium supplementation allows the requisite lowering of blood pressure using smaller doses of the channel blocker while obtaining a greater anti-hypertensive effect. By "calcium channel blockers" is meant any pharmaceutical composition which inhibits the entry of calcium cells or inhibits the mobilization of calcium from intracellular cells. Representative examples of useful calcium channel blockers are dihydropyridines such as nifedipine and benzeneacetonitriles such as verapamil. As a result, not only is the therapy improved and side effects reduced, but the cost of treatment may be dramatically lowered, because the cost of calcium supplementation is much lower than the cost of available calcium channel blockers.
An effective alternative to the administration of calcium supplements, particularly when the diet contains adequate calcium, is to administer an effective form of Vitamin D, such as 1α,25-(OH)2 D3, to increase calcium uptake in the duodenal mucosa. When calcium and/or 1α,25-(OH)2 D3 is administered in combination with a calcium channel, it is preferable that the active components be combined in a single capsule containing appropriate unit doses of each. Patient compliance is improved when only one "medicine" is required.
The use of combination therapy involving a calcium channel blocker and calcium and/or an effective form of Vitamin D such as 1α,25-(OH)2 D3 reduces the daily dosage of channel blocker required to less than half the dosage usually required, sometimes to as little as one-fifth of the dosage required for the channel blocker alone. The combination is compatible with other pharmaceutical compounds used for control of hypertension and angina such as angiotensin converting enzyme (ACE) inhibitors, β-adrenergic antagonists, nitrates, and diuretics.
A particular advantage of the combination of a calcium channel blocker and either or both of calcium and le,25-(OH)2 D3 is the predictability of the therapy. The dose-response curve for nifedipine is not predictable in an individual patient, and a considerable period of time may be necessary to ascertain the appropriate dosage. The effect of exogenous calcium supplementation is not predictable, depending on numerous factors including rate of uptake, rate of excretion, parathyroid hormone levels and PHF levels. Somewhat surprisingly, therefore, it has been found that the combination of a calcium channel blocker and calcium supplement is not only synergistic, but that the dose response is more predictable. The predictability is especially apparent with benzeneacetonitriles. Although the combined therapy of calcium with a benzeneacetonitrile (e.g., verapamil) is not synergistic but is statistically additive, the data suggest that a lowering of blood pressure is more predictable. In other words, the dose response curve is more linear and there is a smaller standard error when the calcium channel blocker is of the benzeneacetonitrile class. The time period over which a patient must be titrated is shortened and the potential for side effects is reduced because the therapeutic index is effectively raised.
The dosage of a combination pharmaceutical preparation which is used depends upon the needs of the individual patient. Typical formulations would be in capsule, tablet, powder or granular forms containing 1/5 to 1/2 of the conventional dosage of a calcium channel blocker, preferably 5 mg of nifedipine, with 500 mg of calcium carbonate and/or ca. 10-25 USP units (0.05 μg) of 1α,25-(OH)2 D3. With respect to verapamil, in particular, formulations would contain a molar ratio of elemental calcium to verapamil of 5:1 to 500:1, preferably 10:1 to 250:1. The formulations may also contain pharmaceutically acceptable carriers and stabilizers as appropriate.
The present invention also includes kits which are comprised of separate containers, each containing an individual dose blood pressure lowering effective amounts of a calcium compound and a benzeneacetonitrile. The kit may also contain use instructions in the form of a package insert.
The invention is illustrated by the following examples, which are not limitative of the invention. Modification, such as the additional use of α- and β-adrenergic blocking pharmaceuticals, diuretics, and other agents suitable for treatment of hypertension and angina by other mechanistic pathways, as would be understood by those skilled in the art, is within the scope of applicants' invention.
Male rats of the SHR strain, obtained from Harlan Sprague-Dawley, 12 weeks old, were divided into groups of 12 or 24, and were fed prepared diets containing 0.2%, 0.4% and 0.8% elemental calcium, respectively. Also included in the diet were 0, 50, 150 and 300 mg/kg of food of nifedipine. Distilled water was available ad lib. Feeding was continued for 8 weeks and the mean blood pressure of each animal was determined at the end of that time. The data are shown in Table 1.
From Table 1, it can be seen that SHR rats on a normal diet, (0.2% dietary calcium) and which did not receive nifedipine, showed an average blood pressure of 176 mm Hg. The highest dose of nifedipine, 300 mm/kg, resulted in a decrease in blood pressure of approximately 10 mm Hg. Using 4 times the amount of ordinary dietary calcium, the decrease in blood pressure was shown to be measurable, but small. When maximum dietary calcium and nifedipine were coadministered, blood pressure could be reduced to approximately 120 mm Hg, or a decrease of approximately 56 mm Hg, or 32% (the level found in normotensive rats).
Nifedipine in amounts of 50 or 150 mg/kg of food decreased mean blood pressure by 20 mm Hg, but supplementation with 0.8% calcium reduced mean blood pressure by approximately 40 to 60 mm Hg. A combination of nifedipine and dietary supplemental calcium produced a predictable and nearly linear dose response with increased efficacy when compared to either agent alone. The data is suggestive of a synergistic relationship between the two agents.
The substitution of nicardipine for nifedipine produces similar synergistic results.
A capsule containing a calcium channel blocker and a calcium supplement may be prepared using conventional techniques according to the following formulation:
| ______________________________________ |
| Nifedipine 5 mg. |
| CaCO3 500 mg. |
| gelatin (soft) 1,495 mg. |
| ______________________________________ |
A capsule containing a calcium channel blocker and 1α,25-(OH)2 D3 may be prepared using conventional techniques according to the following formulation:
| ______________________________________ |
| Nifedipine 5 mg. |
| 1α,25-(OH)2 D3 |
| 0.05 μg. |
| gelatin (soft) 1,745 mg. |
| ______________________________________ |
Male rats of the SHR strain, obtained from Harlan Sprague-Dawley, 12 weeks old, were divided into groups of 12 or 24, and were fed prepared diets containing 0.2%, 0.4% and 0.8% elemental calcium, respectively. Also included in the diet were 0, 300, 900 and 1800 milligrams per kilogram of food of verapamil. Distilled water was available ad lib. Feeding was continued for 8 weeks and then mean arterial pressure of each animal was determined at the end of that time. The data are shown in Table 2. In Table 2, MAP stands for mean arterial pressure and SHR stands for spontaneously hypertensive rats.
From Table 2, it can be seen that SHR rats on a normal diet (0.2% dietary calcium) and which did not receive verapamil showed an average blood pressure of 156 mm Hg. The highest dose of verapamil, 1800 milligrams per kilogram, resulted in a decrease of blood pressure of approximately 15 mm HG. Using two times the ordinary amount of dietary calcium, the decrease in blood pressure was shown to be measurable and directly dependent on dosage of verapamil. When maximum dietary calcium and verapamil were co-administered, blood pressure could be reduced to approximately 118 mm HG, or a decrease of approximately 38 mm Hg.
A combination of verapamil and dietary supplemental calcium produced a predictable and nearly linear dose response with increased efficacy when compared to either agent alone.
| TABLE 1 |
| ______________________________________ |
| SYNERGISTIC EFFECT OF CALCIUM AND |
| NIFEDIPINE ON BLOOD PRESSURE IN SHR |
| Nifedipine |
| (mg/kg Dietary calcium (% as elemental Ca) |
| food) 0.2% 0.4% 0.8% |
| ______________________________________ |
| 0 176 ± 5 164 ± 6 |
| 169 ± 6 |
| 50 145 ± 7 154 ± 5 |
| 133 ± 7 |
| 150 147 ± 8 136 ± 4 |
| 119 ± 9 |
| 300 167 ± 7 125 ± 7 |
| 118 ± 5 |
| ______________________________________ |
| p < .0001 for calcium effect |
| p < .0001 for nifedipine effect |
| p = .0034 for interaction |
| TABLE 2 |
| ______________________________________ |
| EFFECT OF VERAPAMIL AND CALCIUM |
| ON MAP IN SHR |
| VERAPAMIL |
| (mg/kg DIETARY CALCIUM (% as elemental) |
| food) 0.2 0.4 0.8 |
| ______________________________________ |
| 0 156 ± 6 137 ± 5 |
| 138 ± 9 |
| 300 156 ± 10 |
| 131 ± 9 |
| 159 ± 5 |
| 900 134 ± 8 124 ± 10 |
| 139 ± 7 |
| 1800 141 ± 5 119 ± 6 |
| 118 ± 4 |
| ______________________________________ |
| P = .004 for Verapamil effect |
| P = .006 for calcium effect |
| interaction = NS |
Pang, Peter K. T., Lewanczuk, Richard Z., Benishin, Christine G.
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